Effects of α-glucosidase inhibitors on cytochrome P450

α-葡萄糖苷酶抑制剂对细胞色素P450的影响

• 批准号: 10670344
• 负责人: WANG Peiyu
• 金额: $ 1.47万
• 依托单位: Yamanashi Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670344/
• 关键词: α-glucosidase inhibitor; acarbose; voglibose; CPY; hepatotoxicity; acetaminophen; carbon tetrachloride; diabetes; diabetes; Acarbose; CYP2E1; Hepatotoxicity; Carbon Tetrachlorid; Acetaminophen

We studied the effects of α-glucosidase inhibitors (acarbose and voglivose) on cytochrome P450 (CYP) and hepatotoxicity Of carbon tetrachloride (CClィイD24ィエD2) and acetaminophen (AP) in rats, both of which exert their toxic effects through bioactivation associated with CYP2E1. We began the study with acarbose. Male Sprague-Dawley rots were kept on a daily ration (20 g) of powdered chow diet containing 0, 20, 40 or 80 mg/100 g of acarbose, with drinking water containing 0 or 10% of ethanol (v/v). Three weeks later, the rats were either killed for an in vitro metabolism study or challenged with 0.50 g/kg CCl ィイD24ィエD2 po or 0.75 g/kg AP ip. The ethanol increased the hepatic microsomal CYP2E1 level and the rate of dimethylnitosamine (DMN) demethylation. The 40 or 80 mg/100 g acarbose diet, which alone increased the CYP2E1 level and the rate of DMN demethylation, augmented the enzyme induction by ethanol. The 40 or 80 mg/100 g acarbose diet alone potentiated CClィイD24ィエD2 and AP hepatotoxicity, as evidenced by significantly increased levels of both ALT and AST in the plasma of rots pretreated with acarbose. Ethanol alone also potentiated the toxicity of both chemicals. When the 40 or 80 mg/100 g acarbose diet was combined with ethanol, the ethanol-induced potential/on of CCィイD24ィエD2 and AP hepatotoxicity was augmented. We performed the similar experiment on voglivose and found it (5.0 or 10.0 mg/100 g diet, 3 weeks) induced CYP2E1 and increased hepatotoxicity of CCィイD24ィエD2 (0.50 g/kg). Our study demonstrated that high doses of α-glucosidase inhibitors can potentiate CClィイD24ィエD2 and AP hepatotoxicity in rats by inducing hepatic CYP2E1.

本文研究了α-葡萄糖苷酶抑制剂阿卡波糖和伏格列沃糖对大鼠细胞色素P450（CYP）和四氯化碳（CCl_2D_24）及对乙酰氨基酚（AP）肝毒性的影响。我们从阿卡波糖开始研究。雄性Sprague-Dawley rot保持每日配给（20 g）含有0、20、40或80 mg/100 g阿卡波糖的粉状食物饮食，饮用水含有0或10%乙醇（v/v）。3周后，处死大鼠进行体外代谢研究，或用0.50 g/kg CCl-24-D2 po或0.75 g/kg AP ip激发。乙醇可增加肝微粒体CYP 2 E1水平和二甲基亚硝胺（DMN）去甲基化速率。40或80 mg/100 g阿卡波糖饮食，单独增加CYP 2 E1水平和DMN去甲基化速率，增强乙醇的酶诱导。单独40或80 mg/100 g阿卡波糖饮食增强了CCl-24-D2和AP肝毒性，这通过阿卡波糖预处理的腐烂动物血浆中ALT和AST水平的显著增加来证明。单独的乙醇也增强了这两种化学物质的毒性。当40或80 mg/100 g阿卡波糖饮食与乙醇结合时，CC β D24 β D2和AP肝毒性的乙醇诱导潜力增加。我们对伏格列沃糖进行了类似的实验，发现它（5.0或10.0 mg/100 g饲料，3周）诱导CYP 2 E1，并增加CC-24-D2（0.50 g/kg）的肝毒性。我们的研究表明，高剂量α-葡萄糖苷酶抑制剂可通过诱导肝脏CYP 2 E1而增强大鼠的CCl-24-D24-D2和AP肝毒性。

项目成果

王培玉 金子誉 佐藤章夫: "糖尿病治療薬ボグリボースによる肝チトクロムP450の誘導および四塩化炭素肝毒性の増強"産業衛生学雑誌. (2000)

Peiyu Wang、Homare Kaneko 和 Akio Sato：“抗糖尿病药物伏格列波糖诱导肝细胞色素 P450 并增强四氯化碳肝毒性”《工业卫生杂志》（2000 年）。

Wang P-Y, Kaneko T, Wang Y, Sato A: "Acarbose alone or in combination with ethanol potentiates the hepatotoxicity of carbon tetrachloride and acetaminophenin in rat"Hepatology. 29(1). 161-165 (1999)

Wang P-Y、Kaneko T、Wang Y、Sato A：“阿卡波糖单独使用或与乙醇联合使用会增强四氯化碳和对乙酰氨基酚对大鼠的肝毒性”肝病学。

Wang P-Y, Kaneko T, Wang Y, Sato A: "Acarbose alone or in combination. With ethanol potentiates the hepatotoxicity of carbon tetrachloride and acetaminoph in rats."Hepatology. 29(1). 161-165 (1999)

Wang P-Y、Kaneko T、Wang Y、Sato A：“阿卡波糖单独或组合使用。与乙醇一起会增强四氯化碳和对乙酰氨基酚对大鼠的肝毒性。”肝病学。

王倍玉、金子誉、佐藤章夫: "糖尿病治療薬ボクりボースによる肝チトクロムP450の誘導および四塩化炭素肝毒性の増強"産業衛生学雑誌. (2000)

王振宇、Homare Kaneko 和 Akio Sato：“抗糖尿病药物 Bokuribose 诱导肝细胞色素 P450 并增强四氯化碳肝毒性”《工业卫生杂志》（2000 年）。

Wang Pei-Yu et al.: "Acarbose Alone or in Combination with Ethanol Potentiates the Hepatotoxicity of Carbon Tetrachloride and Acetaminophen in Rats" Hepatoloty. 29(1). 161-165 (1999)

Wang Pei-Yu 等人：“阿卡波糖单独使用或与乙醇联合使用可增强四氯化碳和对乙酰氨基酚对大鼠的肝毒性”肝病学。